Board Review: Genetics January 2008

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Karyotypes Diagnosis?

Karyotypes Diagnosis?

Endocardial cushion defect Special Olympics: Atlantoaxial instability Down Syndrome/Trisomy 21 Full trisomy 21 94% Mosaic trisomy 21 2.4% Translocation 3.3% Translocations Parent carrier t(21q;21q) 100% recurrence Parent carrier t(14q;21q) 1/3 chance of having affected child IF THE PATIENT HAS A TRANSLOCATION THE PARENTS KARYOTYPE SHOULD BE CHECKED Heart defect: Endocardial cushion defect Special Olympics: Atlantoaxial instability

Risk Table for Down Syndrome Maternal Age Prevalence at Live Birth 25 1/1350 30 1/890 35 1/355 40 1/97 45 1/23 Note from Caroline: You need to know these numbers cold! Note from Rachel: I’d rather memorize developmental milestones or stick a fork in my eye!

CRANIOSYNOSTOSIS Simple 1 fused suture Complex > 1 suture premature fusion of 1 or more cranial sutures, often resulting in an abnormal head shape Simple 1 fused suture Complex > 1 suture Syndromic Complex+other malformations Should be recognized before 5 mo of age

What cutaneous finding is associated with Crouzon syndrome? The craniofacial syndrome associated with cervical spine fusion, OM, and syndactyly. Aperts 71% of patients with this CFS have Chiari I type malformations and hydrocephalus Crouzon What cutaneous finding is associated with Crouzon syndrome? Acanthosis nigricans Which CFS is associated with medially deviated great toes & broad radial thumbs? Pfeiffer Syndrome

SYNDROMIC CRANIOSYNOSTOSIS Apert Syndrome Crouzon Syndrome Pfeiffer syndrome

What genetic syndrome would this make you think of? Trisomy 13 What is the most common congenital heart defect? VSD

Brain (Holoprosencephaly, microcephaly, punched out scalp lesions Patau Syndrome/Trisomy 13 Brain (Holoprosencephaly, microcephaly, punched out scalp lesions Air (Low set ears, malformed ears) Digits (polydactyly) Leukocytes (unique projections in neutrophils) Uterus (Bicornate uterus and hypoplastic ovaries) Cleft lip and palate Kidneys (cystic) Most common CHD? VSD 80%

Nl What does this girl have? Turner Syndrome

You see a baby in the NICU with feet like this… What lab test would confirm the diagnosis? Chromosomes (45, XO)

Most common cardiac defect in TS Coarctation of the aorta. Turner Syndrome / 45,X0 Short stature, webbed neck, delayed secondary sexual characteristics, short 4th-5th metacarpals, widely space nipples, pedal edema, cubitus valgus Most common cardiac defect in TS Coarctation of the aorta. It is the most common chromosomal defect in spontaneous abortions

Short sternum, prominent occiput, microcephaly. Edwards Syndrome/Trisomy 18 Short sternum, prominent occiput, microcephaly. Clenched fists, hypoplastic nails Horseshoe Kidney Rocker bottom feet

Holt-Oram Syndrome Inheritance Autosomal Dominant Diagnostic criteria: Abnormalities of the thumb triphalangia hypoplasia aplasia Congenital heart disease. atrial septal defects arrhythmia

What diagnosis should you suspect? A 4 year old boy presents because he’s been falling a lot per his parents. His dad is mad because the child “walks like a girl on his tippy toes.” What diagnosis should you suspect? Duchenne’s Muscular Dystrophy Can someone demonstrate a physical exam finding seen in this disease? Gower sign What would be the diagnostic finding on muscle biopsy? Absence of dystrophin

Duchenne Muscular dystrophy is the most common hereditary muscular disease, a X linked recessive disorder inherited by more than 1:4000 boys. Pseudohypertrophy of the calves Gower sign

Patient started having difficulties in school when he was eight years old. His teacher noted that he seemed to be irritable and impulsive; she raised the possibility of attention deficit disorder. In addition, Ronnie was noted to have mild difficulties with spelling and composition. Although he was requiring some additional help with these tasks, his IQ was normal (104) and he had been progressing academically with his peer group. He was tall for his age (95th percentile in height). He had no physical or medical problems. A detailed evaluation by a psychologist revealed some impulsivity, but insufficient findings to support a diagnosis of attention deficit disorder. Tutoring was arranged, and he continued to progress adequately in school. At age 14 years, he develops gynecomastia. At this point, he is seen by an endocrinologist. What is the diagnosis ? Klinefelter Syndrome Treatment: TESTOSTERONE

You also need to know Normal testicular volume Age, yr Length, cm (mean ± SD) Volume, mL (approximate) < 2 1.4 ± 0.4   2 - 4 1.2 ± 0.2 4 - 6 1.5 ± 0.6 1 6 - 8 1.8 ± 0.3 8 - 10 2.0 ± 0.5 2 10 - 12 2.7 ± 0.7 5 12 - 14 3.4 ± 0.8 10 14 - 16 4.1 ± 1.0 20 16 - 18 5.0 ± 0.5 29 18 - 20 5.0 ± 0.3

Café au Lait spot with irregular borders like the coast of Maine McCune Albright Syndrome Café au Lait spot with irregular borders like the coast of Maine Precocious Puberty Appearance of physical and hormonal signs of pubertal development at an earlier age than is considered normal Males <9 years Females < 8 years polyostotic fibrous dysplasia : abnormal fibrous tissue growth in many bones. Normal bone is replaced by irregular masses of fibroblast cells.

Cri du Chat/ Deletion 5p One of the most common human deletion syndromes with an incidence 1 in 20,000 to 1 in 50,000 births The syndrome was discovered in France in 1963 by a team headed by the late Jerome Lejeune. The peculiar cry of affected infants sounded to Lejeune like the meowing of a Parisian cat. The syndrome involves severe developmental and mental retardation and a characteristic constellation of congenital malformations: microcephaly round face hypertelorism micrognathia epicanthal folds low-set ears hypotonia motor and mental retardation Although the majority of patients die in early childhood, some survive into adulthood and exhibit an IQ below 20.

This girl has hearing problems but otherwise does well in school. What is her diagnosis? Treacher Collins What might clue you in on family history? Multiple family members with hearing aids

Noonan Syndrome AKA as Male Turner, but don’t be fooled it can be present in females due to AD inheritance. Clinical Features Short stature Congenital heart defect (Pulmonary Stenosis) Webbed neck Superior pectus carinatum, inferior pectus excavatum, Apparently low-set nipples; Developmental delay of variable degree; Cryptorchidism; Characteristic facies: low-set, posteriorly rotated ears; vivid blue or blue-green irises; wide-spaced eyes with epicanthal folds thick or droopy eyelids. Coagulation defects 3 genes associated: PTPN11, KRAS, SOS1

What other complications is he at risk for? You have an obese 6 year old male who was brought in because his mom is frustrated that he is always waking up and stealing food from the kitchen at night even though he’s on a diet. What is the mechanism of action for the diabetes he will likely develop? It’s type 2 DM due to insulin resistance What other complications is he at risk for? GH deficiency, hypogonadism, osteoporosis, hypothyroidism, SCFE, sleep apnea….

Hypotonia, Obesity, small hands and feet Prader-Willi Syndrome Hypotonia, Obesity, small hands and feet Etiology Deletion 15q11-q13 75% cases Maternal UPD 20% cases Imprinting mutation 5% cases

Profound speech impairment Ataxia and other movement disorders Angelman Syndrome Clinical Features Severe DDM Profound speech impairment Ataxia and other movement disorders Inappropriate laughter Short attention span Microcephaly and seizures Wide spaced teeth Hypopigmentation Remember IMPRINTING 2 alleles from MOM PWS 2 alleles from DAD AS

Beckwith Wiedemann Syndrome Clinical Features Macroglossia Omphalocele Macrosomia Hypoglycemia Hemihypertrophy Hypospadias Indentation on posterior helix

DiGeorge Syndrome/ Deletion 22q11.2/VCF Inheritance autosomal dominant Clinical Features aplasia or hypoplasia of the thymus (immunodeficiency) aplasia, or hypoplasia of the parathyroid glands (Hypocalcemia) conotruncal cardiac defects Hearing loss, CL/CP, velopharyngeal incompetence, prominent nose, narrow alae nasi, long face Slender fingers What lab test makes the diagnosis: FISH 22q VSD (62%) R AoArch (52%), TOF (21%)

You would use FISH to detect all of the following syndromes except: Prader willi Edwards Velocardiofacial Williams Cri du chat All of them are deletions except Edwards (check chromosomes)

Supravalvular Ao stenosis Williams Syndrome Mental retardation, dysmorphic facies, infantile hypercalcemia, growth deficiency, cocktail personality, hoarse voice, enamel hypoplasia Supravalvular Ao stenosis

Mild to moderate microcephaly Short palpebral fissures Epicanthal folds Short nose mid face hypoplasia Thin/smooth upper lip Long philtrum Prenatal and postnatal growth delay Neurodevelopmental deficits Fetal Alcohol Syndrome